Taste-making compositions of ranitidine

ABSTRACT

This invention relates to a composition which is substantially free of the bitter taste associated with ranitidine and comprises: a) a dispersion of lipid coated particles of ranitidine or a physiologically acceptable salt thereof in a non-aqueous vehicle; b) particles comprising ranitidine or a physiologically acceptable salt thereof incorporated into a core and coated with a lipid coating; c) lipid coated particles of a form of ranitidine which is poorly soluble in water; and processes for the preparation thereof and pharmaceutical compositions thereof.

This application is a 371 of PCT/EP93/02832 filed on Oct. 14, 1993published as WO94/08576 Apr. 28, 1994.

The present invention relates to improvements in the formulation of thehistamine H₂ -receptor antagonist ranitidine, particularly for oraladministration.

Ranitidine,N-[2-[[5-[(dimethylamino)methyl]-2-furanylmethyl]-thio]ethyl]-N'-methyl-2-nitro-1,1-ethenediamine, and its physiologically acceptable salts are describedand claimed in British Patent Specification No. 1565966, and aparticular crystalline form of ranitidine hydrochloride is described andclaimed in British Patent Specification No. 2084580B. In both thesespecifications there is reference to formulations for oraladministration, which may take the form of for example tablets,capsules, granules, powders, solutions, syrups, suspensions, or tabletsor lozenges for buccal administration. Oral preparations of ranitidineare also disclosed in British Patent Specification Nos. 2142820,2198352, 2218336, 2219940, 2222772 and 2229094.

Oral administration constitutes a preferred route for administeringranitidine. Ranitidine, however, in common with many drug substances,has an inherently bitter taste, and this constitutes a disadvantage withcertain types of oral preparation. Moreover, it is well known thatpatients may not complete a necessary course of medicine if they areprescribed an oral presentation which is particularly unpleasant totaste. The problems resulting from the bitter taste of ranitidine areparticularly acute in formulations such as chewable tablets, granules,powders, solutions or suspensions. To some extent, the bitter taste maybe masked by the use of sweetening and/or flavouring agents, althoughthis is not entirely satisfactory, and an unpleasant after-taste maystill remain in the mouth. In addition, there may be circumstances inwhich it is undesirable or inappropriate to use a sweetening and/orflavouring agent.

Various methods of taste-masking ranitidine have been described. Forexample, British Patent Specification No. 2218333 describes complexesformed between ranitidine and an ion exchange resin to give a resinadsorbate which is substantially free of the bitter taste associatedwith ranitidine.

Other methods of taste-masking ranitidine are described in EP349103,EP459695, EP473431 and U.S. Pat. No. 5084278.

We have now found that the bitter taste of ranitidine may be masked bycoating the drug substance with a suitable lipid.

One of the factors that governs the degree of taste masking obtained bylipid coating is the water solubility of the input drug substance. Thus,for forms of ranitidine which are only poorly soluble in water (e.g.less soluble salts of rantidine), the bitter taste associated withranitidine may be satisfactorily masked by simple lipid coating of thedrug substance. In the case of forms of ranitidine which are soluble inwater to an appreciable extent (e.g. ranitidine base and certain of itssalts), the degree of taste masking achieved by simple lipid coating ofthe drug substance may not be entirely satisfactory, particularly if theproduct is to be formulated in an aqueous medium or the product comesinto contact with the wet environment of the mouth. We have found thatthe degree of taste masking achieved by coating the drug substance witha suitable lipid, especially when the ranitidine is in a form having anappreciable solubility in water, can be significantly enhanced if thedrug substance is incorporated into a core prior to being coated withthe lipid.

The resulting lipid coated particles, containing an inner core ifrequired, are substantially insoluble in water but break down on contactwith gastrointestinal fluid, such that the bitter taste associated withranitidine is masked on oral administration, with subsequent release ofthe drug substance, by dispersion or dissolution, in thegastrointestinal tract.

Thus according to one aspect the present invention provides acomposition which is substantially free of the bitter taste associatedwith ranitidine and comprises

a) a dispersion of lipid coated particles of ranitidine or aphysiologically acceptable salt thereof in a non-aqueous vehicle

b) particles comprising ranitidine or a physiologically acceptable saltthereof incorporated into a core and coated with a lipid coating

c) lipid coated particles of a form of ranitidine which is poorlysoluble in water.

According to a further aspect, the present invention provides acomposition for oral administration, which is substantially free of thebitter taste associated with ranitidine and comprises a dispersion oflipid coated particles of ranitidine or a physiologically acceptablesalt thereof in a non-aqueous vehicle.

According to a yet further aspect, the invention provides a method ofmasking the bitter taste associated with ranitidine which comprisescoating ranitidine or a physiologically acceptable salt thereof with asuitable lipid, and incorporating the lipid coated particles into anon-aqueous composition.

According to a yet further aspect the present invention providesparticles for oral administration, comprising ranitidine or aphysiologically acceptable salt thereof, optionally incorporated into acore, coated with a coating of a lipid, which particles aresubstantially free of the bitter taste associated with ranitidine.

According to a further aspect, the invention provides a method ofmasking the bitter taste of ranitidine which comprises coatingranitidine or a physiologically acceptable salt thereof, optionallyincorporated into a core, with a suitable lipid.

Ranitidine may be employed according to the invention in the form ofeither its free base or a physiologically acceptable salt. Such saltsinclude salts with inorganic or organic acids such as the hydrochloride,hydrobromide, sulphate, acetate, maleate, succinate, citrate, tartrate,fumarate and ascorbate salts. A particularly preferred salt ofranitidine is the hydrochloride.

Suitable lipids for the outer coating include fatty acids or monohydricalcohols thereof, fixed oils, fats, waxes, steroIs, phospholipids andglycolipids either singly or in mixture. The lipid may, for example, bea high molecular weight (C₁₀ -C₃₀) straight chain saturated orunsaturated aliphatic acid, such as palmitic or stearic acid; a mono-di- or tri- high molecular weight (C₁₀ -C₃₀) aliphatic acid ester ofglycerol, such as glyceryl tripalmitate, glyceryl tristearate or a mixedacid ester triglyceride; partially hydrogenated vegetable or animal oilssuch as hardened palm oil or hardened edible tallow; high molecularweight (C₁₀ -C₃₀) straight chain aliphatic alcohols such as stearylalcohol or cetyl alcohol; microcrystalline waxes consisting ofstraight-chain, branched-chain or cyclic hydrocarbons with averagemolecular weight 580 to 900; or a mixture thereof. Mixtures of lipidsmay also be used, including mixtures of glyceryl esters of highmolecular weight aliphatic acids such as mixtures involving glyceryltrilaurate, glyceryl tristearate, glyceryl tripalmitate and/or mixedacid ester triglycerides; mixtures of high molecular weight aliphaticacids such as mixtures of palmitic acid and stearic acid; mixtures ofpartially hydrogenated vegetable or animal oils and glyceryl esters suchas hardened palm oil and glyceryl tripalmitate and mixtures of glycerylesters with microcrystalline waxes such as glyceryl tripalmitate andmicrocrystalline wax. A particularly preferred lipid mixture is glyceryltristearate in admixture with glyceryl trilaurate in a ratio in therange 9:1 to 1:4, more preferably 4:1 to 1:1, and in particular 3:1, byweight. The most preferred lipid is glyceryl tripalmitate of high purityhaving a low iodine value (preferably less than 1.0) and a low acidvalue (preferably less than 0.5).

The lipid coated particles of the invention will generally have adiameter of less that 1000 microns, preferably less than 500 microns,and more preferably less than 200 microns. Coated particles with adiameter in the range of 1-200 microns e.g. 20-150 microns arepreferred. Control of the particle size is necessary to ensure that thesubsequently formulated product does not produce a "gritty" feel in themouth and particles having a diameter of less than about 150 microns arepreferred in this respect.

The lipid coated particles of the invention may conveniently be preparedby atomising a dispersion of ranitidine or a physiologically acceptablesalt thereof, or a dispersion of core particles containing theranitidine or ranitidine salt, as appropriate, in a molten lipid, andcooling the resultant particles, and such a process constitutes afurther feature of the invention. Atomising techniques which may be usedinclude the use of conventional atomisers such as rotary atomisers,pressure nozzles, pneumatic nozzles and sonic nozzles. The use of atwo-fluid pneumatic nozzle atomiser fitted in a standard spraydrying/chilling apparatus is particularly convenient.

In the atomisation process using a pneumatic two-fluid nozzle atomiser,the molten lipid dispersion will generally be supplied to the atomiserhead at a temperature in the range of 60° to 90° C., preferably 70° to80° C., the precise temperature depending on the particular lipid used.The atomising gas supplied to the nozzle may be air or an inert gas suchas nitrogen. The temperature of the gas will generally be within therange 70° to 100° C., preferably 75° to 85° C. with the precisetemperature dependant upon the particular lipid material being used. Ithas been found that, in the coating process, the temperature at whichthe molten lipid dispersion is maintained is preferably in the range of10° to 20° C. above the melting point of the lipid. The atomisingpressure is desirably controlled in order to produce particles of apreferred size.

The molten dispersion may be prepared by dispersing the ranitidine orranitidine salt, or core particles containing the ranitidine orranitidine salt, as appropriate, in the molten lipid or mixture oflipids using conventional techniques. When the input drug substance hasnot been incorporated into cores, a high shear mixer may be used. Whenthe input drug substance has been incorporated into cores prior to lipidcoating, a low shear mixer should be used, to avoid disruption of thecores. In general, the lipid or lipid mixture used for the outer coatingshould have a melting point within the range of 30° to 100° C.,preferably 40° to 85° C., and the temperature of the molten lipid willbe 10° to 20° C. above its melting point. However, when overcoatingcores which have been prepared by coating the input drug substance witha lipid or wax having a melting point which is higher than that of theouter lipid coating (as described hereinafter), the lipid or lipidmixture used for the outer coating preferably has a melting point of 40°to 60° C., and care must be taken not to allow the temperature of themixture to rise above 10° C. below the melting point of the lipid or waxused to form the core.

The ranitidine content of the lipid coated particles may be, forexample, in the range of 1 to 80%, preferably 10 to 70%, more preferably15 to 50% on a weight-to-weight (w/w) basis, the ranitidine being in theform of the free base or a physiologically acceptable salt, mostpreferably in the form of ranitidine hydrochloride.

When the ranitidine is in a form which is soluble in water to anappreciable extent (e.g. in the form of ranitidine hydrochloride), suchthat it is necessary to incorporate the drug substance into inner coresprior to lipid coating, the final ranitidine content of the lipid coatedparticles will depend upon the input level of ranitidine in the coreparticles. When lipid coating cores containing the ranitidine orranitidine salt, the cores may be dispersed in the molten lipid in anamount within the range of for example 1 to 80% by weight, preferably 20to 70% by weight, and more preferably 30 to 60% by weight. The lipidprovides the remainder of the weight of the molten dispersion.

When it is necessary to incorporate the drug substance into inner cores,the cores for subsequent lipid coating, which constitute a furtheraspect of the invention, comprise a dispersion of the ranitidine or aphysiologically acceptable salt thereof (e.g. ranitidine hydrochloride)in either a polymeric binder, or a lipid or wax having a melting pointwhich is higher than that of the outer lipid coating. The cores arepreferably spherical in shape and ideally have a particle sizeapproaching that desired for the final lipid coated product. This allowsthe application of a discrete overcoat of lipid or mixture of lipids toeach drug particle thereby fully encapsulating the drug core andsatisfactorily masking the taste of ranitidine.

Suitable polymeric binders for use in the drug cores includealkylcelluloses such as methylcellulose, ethylcellulose,propylcellulose; hydroxyalkylcelluloses (e.g. hydroxypropylcellulose orhydroxypropylmethylcellulose) and other cellulose based polymers (e.g.hydroxypropyl methylcellulose phthalate); polyvinylpyrrolidone; andpolymer systems based on methacrylic acid or other acrylate polymers.Ethylcellulose is particularly preferred.

Cores comprising ranitidine or a physiologically acceptable salt thereofand a polymeric binder may be prepared by spray drying a suspension ofthe drug substance dispersed in a solution of the polymer in a suitablesolvent. A suitable solvent is one in which the polymer is soluble, butthe ranitidine or ranitidine salt is essentially insoluble. Particularlysuitable solvents include a mixture of dichloromethane and ethanol.

The ratio of ranitidine to polymer in the suspension (the ranitidinebeing in the form of its free base or a physiologically acceptable salt)may be in the range 5:95 to 95:5, preferably 30:70 to 90:10, and morepreferably 60:40 to 80:20, on a weight-to-weight (w/w) basis. Thesuspension or solution to be spray dried should contain 5 to 80% w/wsolids (i.e. ranitidine or ranitidine salt together with polymer)preferably 10 to 60% w/w and more preferably 20 to 40% w/w. Aparticularly preferred suspension for spray drying contains 20% w/wranitidine hydrochloride suspended in a solution of 10% w/wethylcellulose and 3% w/w ethanol in dichloromethane.

The suspension may be spray dried using a conventional spray drier.Atomisation of the suspension may be achieved using either a rotaryatomiser, pressure nozzle, pneumatic nozzle or sonic nozzle. The use ofa two fluid external mixing pneumatic nozzle is particularly convenient.In the spray drying process the inlet gas fed into the spray dryer isheated to a temperature sufficient to remove the solvent from thedroplets of atomised suspension or solution to produce sphericalparticles of the drug substance and the chosen polymer. For example,with a dichloromethane solvent system the temperature of the gasentering the chamber is preferably in the range 50° to 150° C.,preferably 70° C. to 120° C. and more preferably 80° C. to 100° C. Inaddition to controlling the temperature of the chamber gas in the spraydrying process it is necessary to control the feed rate and atomisationconditions for the suspension or solution to produce particles of therequired shape and size. The preferred shape of the particles so formedis spherical. The presence of irregular shaped particles reduces theeffectiveness of subsequent overcoating procedures in masking the bittertaste of the drug. The size of the particles is also important. Theparticles preferably have a diameter of less than 200 microns, morepreferably in the range 5 to 100 microns.

In order to obtain lipid coated particles, or core particles forsubsequent lipid coating, of the required size, it is necessary toreduce the particle size of the input drug substance. This may beachieved using several techniques including fluid energy milling, hammermilling, pin milling and ball milling. The process of pin milling ispreferred and may be used, for example, to reduce the particle size ofranitidine hydrochloride to less than 150 microns and preferably lessthan 100 microns. Alternatively the particle size may be reducedsufficiently during the spray chilling procedure by high shear mixing ofthe molten mixture following dispersion of the input drug substance inthe molten lipid(s). This may be achieved, for example, using aSilverson mixer fitted with a high shear square hole screen.

Where the cores for subsequent lipid coating comprise a dispersion ofranitidine or a physiologically acceptable salt thereof in a lipid orwax having a melting point which is higher than that of the outer lipidcoating, the lipid or wax used for the core may have a melting point offor example 80° C. or above, in order to prevent melting of the coreduring the subsequent lipid coating process. Suitable lipids or waxesused in forming the cores include triglycerides of long chain saturatedfatty acids; long chain fatty acids; long chain fatty alcohols;microcrystalline waxes consisting of straight-chain, branched-chain andcyclic hydrocarbons; or mixtures of these, suitably chosen (havingregard to melting point) from the types of lipids listed previously. Inthe case of ranitidine hydrochloride, for example, the naturallyoccurring wax, carnauba wax, is particularly preferred.

The dispersion may be formed by melting the lipid or wax and raising thetemperature of the molten material to 20° C. to 30° C. above its meltingpoint. To this is then added the ranitidine or ranitidine salt of asuitably low particle size, to give a solids content in the moltendispersion of 20 to 80% w/w, preferably 40 to 70% w/w and morepreferably 50 to 70% w/w. A particularly preferred dispersion comprises60% w/w ranitidine hydrochloride in carnauba wax.

The molten dispersion is then spray chilled as described previouslyusing atomising air heated to a temperature approximately 20° to 30° C.above the melting point of the lipid or wax. Generally there is no needto chill the inlet air in the spray chiller. The product is collected asa free flowing powder using either a cyclone separator or bag filter.The particles are spherical in shape and have a particle size preferablyless than 200 microns and more preferably in the range 5 to 100 microns.

Particularly preferred lipid coated particles according to the inventioncomprise cores consisting of ranitidine hydrochloride in anethylcellulose matrix overcoated with glyceryl tripalmitate.

A preferred lipid coated product for suspension in a non-aqueous vehiclecomprises particles of ranitidine hydrochloride coated with a mixture ofglyceryl tristearate and glyceryl trilaurate or, more preferably, withglyceryl tripalmitate.

The lipid coated particles of the invention may be incorporated into apharmaceutical composition for oral administration, using one or morephysiologically acceptable carriers or excipients.

The amount of ranitidine, preferably in the form of a physiologicallyacceptable salt, particularly ranitidine hydrochloride, in the oralformulation is preferably in the range of 10 to 800 mg per dosage unit,e.g. 20 to 600 mg, more preferably 25 to 300 mg, such as 25, 75, 125 or150 mg, expressed as the weight of free base.

The unit dose may be administered up to, for example, 6 times a daydepending upon the unit dose used, the nature and severity of theconditions being treated, and the age and weight of the patient. Thus,for example, in the treatment of minor conditions where there is anadvantage in lowering gastric acidity such as, for example, acidindigestion, over-indulgence of food or drink, acid stomach, sourstomach, heartburn, such as episodic heartburn, nocturnal heartburn, andmeal-induced heartburn, gastritis and dyspepsia, lower and more frequentdoses of ranitidine may be used, for example doses in the range of10-150 mg, e.g. 25-75 mg ranitidine expressed as the weight of freebase, administered up to 6 times a day as and when required. For moreserious conditions such as duodenal and gastric ulceration, refluxoesophagitis and Zollinger-Ellison syndrome, higher and less frequentdoses of ranitidine will be employed, for example 75-600 mg, e.g. 150 mgunit doses administered one to four, preferably once or twice, daily.

The compositions according to the invention may for example take theform of tablets, capsules, granules, powders, tablets or lozenges forbuccal administration, or liquid preparations such as suspensions.Chewable or suckable tablets, granules, and suspensions representparticularly preferred dosage forms. Granules may be ingested directly,taken with for example a draught of water, or dispersed in water (if theranitidine is in a form which is poorly soluble in water) or othersuitable vehicle prior to administration. The suspensions may benon-aqueous and, in the case of forms of ranitidine which are poorlysoluble in water, the lipid coated material may also be formulated as anaqueous suspension.

The pharmaceutical compositions according to the invention, comprising adispersion of lipid coated particles of ranitidine or a physiologicallyacceptable salt thereof in a non-aqueous vehicle, formulated for oraladministration, may be presented in the form of, for example,non-aqueous suspensions, chewable soft gelatin capsules, or chewabletablets. Non-aqueous suspensions are preferred.

The compositions may be formulated using conventional pharmaceuticallyacceptable carriers or excipients.

Thus for example granules may be prepared by granulating the lipidcoated particles with a binding agent using well known pharmaceuticalgranulation techniques, more particularly fluidised bed granulation.Suitable binding agents include an alkylcellulose orpolyvinylpyrrolidone, more preferably hydroxypropylmethylcellulose. Itmay also be beneficial to add a small amount of a pharmaceuticallyacceptable surface active agent (e.g. sodium lauryl sulphate) to thegranulating fluid to aid the wetting of the particles. The granules aredried using conventional pharmaceutical drying techniques taking carenot to allow the temperature of the granules to rise to within about 10°C. of the melting point of the outer lipid coating.

Tablets of the lipid coated particles may be obtained by compressing thegranules. Alternatively a dry mix of the various excipients used forgranule formation could be compressed together with suitable bindingagents e.g. polyvinylpyrrolidone. Chewable tablets may be preparedincorporating the lipid coated particles with a suitable chewable basesuch as sucrose, glucose, lactose, maltose or a mixture thereof,preferably sucrose, according to conventional procedures. Cast chewabletablets may be prepared by incorporating the lipid coated particles intolow melting point fatty bases. The chosen fatty base should have amelting point that is sufficiently high to give a solid tablet at roomtemperature and preferably at temperatures up to 30° C. but not too highso as to cause melting of the outer lipid coating during processing orto reduce the bioavailability of the drug. Suitable bases are forexample macrogols, fatty acids, mono- di- and tri-glycerides, alkanes,and fatty alcohols either alone or in admixture. In the case ofranitidine hydrochloride, for example, particularly preferred fattybases are suppository bases which melt at about 37° C. and arepharmaceutically acceptable e.g. hard fat and theobroma oil.

Suitable non-aqueous vehicles for use in the compositions according tothe invention, particularly non-aqueous suspensions and chewable softgelatin capsules, include fractionated coconut oil fractionated coconutoil cross-linked with an organic acid such as succinic acid, arachisoil, sesame oil, soya oil and other animal vegetable or synthetic oilssuitable for oral administration, used either singly or in admixture.

Aqueous suspensions may be obtained by dispersing the lipid coatedparticles in an aqueous vehicle. Suitable vehicles include sucrosesyrup; hydrogenated sucrose syrup; sorbitol solution and concentratedsolutions of other sugars; aqueous solutions thickened with cellulosebased polymers such as hydroxypropylmethyl cellulose, methylcellulose ormicrocrystalline cellulose in suspension; aqueous solutions thickenedwith polysaccharides such as starch; aqueous solutions thickened withpolyacrylates such as carbopol; and aqueous solutions thickened withcolloidal dispersing agents such as magnesium aluminium silicate.Various pharmaceutically acceptable excipients such as preservatives andbuffer salts may also be included. In addition, surface active agentsmay be added to aid wetting of the lipid coated particles.

The various preparations may also contain bulk sweeteners (e.g.sucrose), intense sweeteners (e.g. sodium saccharin or aspartame) and/orflavouring agents as appropriate.

The compositions according to the invention may, if desired, beadministered in combination with one or more other therapeutic agents,for example the compositions may also contain a suitable antacid such ascalcium carbonate.

The following Preparations 1 and 2 illustrate the preparation of coreparticles according to the invention containing ranitidinehydrochloride. Ranitidine in the form of its free base or aphysiologically acceptable salt may be incorporated into cores in asimilar manner.

PREPARATION 1

Ethylcellulose (250 g) was dissolved in dichloromethane (1000 g)containing ethanol (72 g). To this was added ranitidine hydrochloride(500 g) of a low particle size (less than 100 microns) dispersed indichioromethane (780 g). The suspension was mixed under high shear untilhomogeneous, and then pumped into a spray drier at a flow rate ofapproximately 260 g/minute and atomised using an external mixingtwo-fluid pneumatic nozzle (dimensions 80/150/180 thousandths of aninch) with an atomising air pressure of 60 psi. The temperature of inletair into the chamber was 85° C. The product was collected using acyclone separator and was composed of mostly spherical particles in thesize range 1 to 300 microns with most of the material having a particlediameter of less than 200 microns.

PREPARATION 2

Carnauba wax (prime yellow grade) (400 g) was melted and heated to 100°C. To this was added milled ranitidine hydrochloride (600 g) of a lowparticle size (less than 100 microns) and this was dispersed by mixingwith a paddle. The molten dispersion at 100° C. was spray chilled at arate of approximately 500g/minute using an internal mixing two-fluidpneumatic nozzle fed with atomising air at a pressure of 60 psi and atemperature of 100° C. The solidified product was collected and found tocomprise spherical particles up to 300 microns in diameter. Particlesgreater than 200 microns were removed by sieving.

The following Examples 1, 2 and 3 illustrate the preparation of lipidcoated particles according to the invention, in which cores as describedin Preparations 1 and 2 are overcoated with lipid.

EXAMPLE 1

Glyceryl tristearate (525 g) and glyceryl trilaurate (175 g) were meltedtogether and raised to a temperature of 75° C. To the molten lipids wasadded spray dried ranitidine hydrochloride-ethylcellulose core particles(300 g) containing 66.6% w/w ranitidine hydrochloride. The moltendispersion was mixed to give a homogeneous suspension and pumped into aspray dryer/chiller apparatus (chamber height 2 m) at a rate ofapproximately 500 g/minute and atomised using an external mixingtwo-fluid pneumatic nozzle (with nozzle dimensions 100/150/180thousandths of an inch) and atomising air at a temperature approximately20° C. above the melting point of the lipid mixture and an atomisingpressure of 60 psi. The product was chilled using air fed into the spraychamber at a temperature of 14° C. and the solid product collected in acyclone separator. The product had a particle size range of 1-300microns with the majority of the particles with diameters less than 200microns. The final ranitidine hydrochloride content was 20% w/w and thematerial was substantially tasteless.

EXAMPLE 2

Glyceryl tripalmitate (200 g) was melted and raised to a temperature of72° C. To this was added ranitidine hydrochloride- carnauba wax coreparticles (100 g) containing 60% w/w ranitidine hydrochloride. The coreparticles were mixed in using a paddle to give a homogeneous suspensionand the temperature of the dispersion maintained at 72° C. The moltendispersion was then spray chilled at a rate of about 500 g/minute asdetailed above using an internal mixing two-fluid pneumatic nozzle withan atomising air pressure of 60 psi and temperature of 73° C. Theresulting particles had a particle size range of about 1 to 300 micronswith the majority of the particles having diameters less than 200microns. The final ranitidine hydrochloride content was 20% w/w and thematerial was substantially tasteless.

EXAMPLE 3

Glyceryl tripalmitate (350 g) was melted and raised to a temperature of75° C. To the molten lipid was added spray dried ranitidinehydrochlorideethylcellulose core particles (150 g) containing 66.6% w/wranitidine hydrochloride. The molten dispersion was mixed to give ahomogeneous suspension and pumped into a spray dryer/chiller apparatus(chamber height 2 m) at a rate of approximately 500 g/minute andatomised using an external mixing two-fluid pneumatic nozzle (withnozzle dimensions 100/150/180 thousandths of an inch) and atomising airat a temperature approximately 20° C. above the melting point of thelipid mixture and an atomising pressure of 60 psi. The product waschilled using air fed into the spray chamber at a temperature of 14° C.and the solid product collected in a cyclone separator. The product hada particle size range of 1-300 microns with the majority of theparticles with diameters less than 200 microns. The final ranitidinehydrochloride content was 20% w/w and the material was substantiallytasteless.

The following Examples 4 and 5 illustrate the preparation of lipidcoated particles of ranitidine hydrochloride. Other physiologicallyacceptable salts, or ranitidine in the form of its free base, may belipid coated in a similar manner, using suitably chosen lipid(s).

EXAMPLE 4

Glyceryl tripalmitate (1200 g) was melted and raised to a temperature of75° C. To this was added ranitidine hydrochloride (300 g). The moltendispersion was mixed to give a homogeneous suspension and pumped to aspray drier/chiller apparatus (chamber height 2 m) at a rate ofapproximately 500 g/minute. The mixture was atomised using an externalmixing two-fluid pneumatic nozzle (with nozzle dimensions 80/150/180thousandths of an inch) and atomising air at a temperature approximately30° C. above the melting point of the lipid and an atomising pressure of50 psi. The atomised droplets were chilled using air fed into the spraychamber at a temperature of 10° C. and the solid product collected in acyclone separator. The product comprised spherical particles with amedian particle size of 120 microns.

EXAMPLE 5

Glyceryl tristearate (900 g) and glyceryl trilaurate (300 g) were meltedtogether and raised to a temperature of 75° C. To this was addedranitidine hydrochloride (300 g). The molten dispersion was subjected tohigh shear mixing using a Silverson high shear mixer for 10 minutes toreduce the ranitidine hydrochloride particle size. This mixture wasspray chilled as described in Example 4, to give a product having asimilar particle size and shape.

The following Examples A, B, C and D illustrate pharmaceuticalcompositions according to the invention in which the lipid coatedparticles are in particular as described in Examples 2 and 3 above.Other types of lipid coated particles according to the invention,containing an inner core into which is incorporated ranitidine free baseor another water-soluble physiologically acceptable salt thereof may beformulated in a similar manner.

EXAMPLE A Flavored Granules

    ______________________________________                                        (i)   Lipid coated ranitidine hydrochloride *                                                               75     g                                              Xylitol (powdered)      120    g                                              Flavour (peppermint)    2      g                                              Granulating fluid **    30     ml                                       ______________________________________                                         * Contains 20% w/w ranitidine hydrochloride as a ranitidine hydrochloride     carnauba wax core overcoated with glyceryl palmitate.                         ** 10% w/v solution of hydroxypropylmethyl cellulose (3 centipoise grade)     in ethanol (85%)/water (15%) mixture.                                    

The solids were mixed and fluidised in a fluid bed granulator. Thetemperature of the bed was raised to 40° C. and the granulating fluidsprayed onto the bed. The resulting granules were dried and screened(1.0 mm sieve). Each 2.24 g of granules contained 168 mg ranitidinehydrochloride (equivalent to 150 mg ranitidine free base) and may betaken dry or first dispersed in water.

    ______________________________________                                        (ii)  Lipid coated ranitidine hydrochloride*                                                                75     g                                              Xylitol (powdered)      120    g                                              Flavour (peppermint)    2      g                                              Granulating fluid**     30     ml                                       ______________________________________                                         *Contains 20% w/w ranitidine hydrochloride as a ranitidine                    hydrochlorideethylcellulose core overcoated with glyceryl tripalmitate.       **10% w/w solution of hydroxypropylmethyl cellulose (3 centipoise grade)      in ethanol (85%)/water (15%) mixture.                                    

The granules were formed as described in Example A (i).

EXAMPLE B Compressed Chewable Tablets

The granules produced in Examples A(i) and A(ii) were mixed with 0.5%w/w magnesium stearate and then compressed using a conventionalpharmaceutical tablet press. Each tablet weighed 2.24 g and contained168 mg ranitidine hydrochloride (equivalent to 150 mg ranitidine freebase).

EXAMPLE C Cast Chewable Tablet

    ______________________________________                                        per tablet                                                                    ______________________________________                                        Lipid coated ranitidine hydrochloride *                                                                 0.84   g                                            Witepsol H15 **           1.8    g                                            Theobroma oil BP          0.36   g                                            Aspartame                 0.01   g                                            Flavour                   0.005  g                                            ______________________________________                                         * Contains 20% w/w ranitidine hydrochloride as a ranitidine                   hydrochlorideethylcellulose core overcoated with glyceryl tripalmitate.       ** Triglyceride suppository base manufactured by Dynamit Nobel.          

The Witepsol H15 and theobroma oil were melted together and heated to36° C. The solids were incorporated and the molten mixture cast intotablet shaped moulds. After solidification the tablets were removed.Each tablet weighed about 3 g and contained 168 g ranitidinehydrochloride.

EXAMPLE D Non-Aqueous Suspension

    ______________________________________                                        Lipid coated ranitidine hydrochloride *                                                                16.8    g                                            Xylitol (powdered)       18.0    g                                            Aspartame                2.0     g                                            Flavour                  q.s.                                                 Fractionated coconut oil to 100  ml                                           ______________________________________                                         * Contains 20% w/w ranitidine hydrochloride as a ranitidine                   hydrochlorideethylcellulose core overcoated with glyceryl tripalmitate.  

The lipid coated ranitidine hydrochloride, xylitol, aspartame andflavour were added to the bulk of the fractionated coconut oil and mixedusing a Silverson mixer fitted with a low shear head. The suspension wasthen made up to volume with fractionated coconut oil and mixed to give ahomogeneous suspension. The dose of ranitidine hydrochloride was 168 mgper 5 ml.

The following Examples E, F and G illustrate non-aqueous pharmaceuticalcompositions according to the invention, in which the lipid coatedmaterial is in particular as described in the above Examples 4 and 5.Other lipid coated materials formed by coating ranitidine or aphysiologically acceptable salt thereof with other types of lipid(s) maybe formulated in a similar manner.

EXAMPLE E Non-aqueous suspension

    ______________________________________                                        (i) For 100 ml                                                                    Glyceryl tripalmitate coated ranitidine                                                                  16.8    g                                          hydrochloride (containing 20% w/w ranitidine                                  hydrochloride)                                                                Aspartame                  2.0     g                                          Mannitol (powdered)        18.0    g                                          Flavour                    q.s.                                               Fractionated coconut oil   to 100  ml                                     ______________________________________                                    

The lipid coated ranitidine hydrochloride, mannitol, aspartame andflavour were added to the bulk of the fractionated coconut oil and mixedusing a Silverson mixer fitted with a low shear head. The suspension wasthen made up to volume with fractionated coconut oil and mixed to give ahomogeneous suspension. The dose of ranitidine hydrochloride was 168 mgper 5 ml (equivalent to 150 mg free base).

    ______________________________________                                        (ii)                                                                              For 100 ml                                                                    Ranitidine hydrochloride (20% w/w) coated                                                               16.8    g                                           with a 3:1 mixture of glyceryl tristerate                                     and glyceryl trilaurate                                                       Xylitol (powdered)        18.0    g                                           Aspartame                 1.5     g                                           Flavour                   q.s.                                                Fractionated coconut oil  to 100  ml                                      ______________________________________                                    

The suspension was prepared by the method described in Example E(i).

EXAMPLE F Chewable soft gelatin capsule

    ______________________________________                                        per capsule                                                                   ______________________________________                                        Ranitidine hydrochloride (30% w/w) coated                                                               0.56   g                                            with glyceryl tripalmitate                                                    Aspartame                 0.03   g                                            Flavour                   q.s.                                                Fractionated coconut oil  0.7    g                                            ______________________________________                                    

The ingredients are mixed, and the mixture filled into soft gelatincapsules.

EXAMPLE G Cast chewable tablet

    ______________________________________                                        per tablet                                                                    ______________________________________                                        Glyceryl tripalmitate                                                                       0.84   g                                                        coated ranitidine hydro-                                                      chloride (containing                                                          20% w/w ranitidine                                                            hydrochloride)                                                                Witepsol H15* 1.8    g     Theobroma oil BP                                                                          0.36 g                                 Aspartame     0.01   g                                                        Flavour       0.05   g                                                        ______________________________________                                         *Triglyceride suppository base manufactured by Dynamit Nobel.            

The Witepsol H15 and theobroma oil are melted together and heated to 36°C. The solids are incorporated and the molten mixture cast into tabletshaped moulds. After solidification the tablets are removed. Each tabletweighs about 3 g and contains 168 g ranitidine hydrochloride (equivalentto 150 mg free base).

We claim:
 1. A composition which is substantially free of the bittertaste associated with ranitidine and comprises particles having a coreand a lipid coating around the core wherein the core comprises adispersion of ranitidine, or a physiologically acceptable salt thereof,in a binder selected from the group consisting of polyvinylpyrrolidone,acrylate polymers and cellulose-based polymers and wherein the lipidcoating comprises lipids selected from the group consisting of fattyacids or monohydric alcohols thereof, fixed oils, fats, sterols,phospholipids, glycolipids and mixtures thereof.
 2. A composition asclaimed in claim 1 wherein the lipid is mono-, di- or tri-C₁₀ -C₃₀aliphatic ester of glycerol or a mixture thereof.
 3. A composition asclaimed in claim 2 wherein the lipid mixture comprises glyceryltristearate in admixture with glyceryl trilaurate in a ratio in therange 9:1 to 1:4.
 4. A composition as claimed in claim 1 wherein theparticles have diameters in the range of 1-200 microns.
 5. A compositionas claimed in claim 1 wherein the ranitidine content of the particles isin the range of 10 to 70% w/w, the ranitidine being in the form of thefree base or a physiologically acceptable salt thereof.
 6. A compositionas claimed in claim 1 containing ranitidine hydrochloride.
 7. A processfor the preparation of a composition as claimed in claim 1 whichcomprises dispersing the cores in a molten lipid, atomizing thedispersion and cooling and collecting the coated cores thereby obtained.8. A pharmaceutical composition for oral administration comprising acomposition as claimed in claim 1, together with one or morephysiologically acceptable carriers or excipients.
 9. A pharmaceuticalcomposition for oral administration comprising a composition as preparedby a process as claimed in claim 7, together with one or morephysiologically acceptable carriers or excipients.
 10. A pharmaceuticalcomposition as claimed in claim 8 in the form of chewable or suckabletablets, chewable soft gelatin capsules, suspensions or granules.
 11. Apharmaceutical composition as claimed in claim 9 in the form of chewableor suckable tablets, chewable soft gelatin capsules, suspensions orgranules.
 12. A pharmaceutical composition as claimed in claim 8containing 10 to 800 mg ranitidine per dosage unit, expressed as theweight of free base.
 13. A pharmaceutical composition as claimed inclaim 9 containing 10 to 800 mg ranitidine per dosage unit, expressed asthe weight of free base.
 14. The composition of claim 1 wherein thebinder has a melting point which is higher than that of the lipidcoating.
 15. The composition of claim 14 wherein the cellulose-basedpolymeric binder is an alkyl cellulose.
 16. The composition of claim 1wherein said composition is an aqueous composition.
 17. The compositionof claim 1 wherein the lipid coating comprises lipids selected from thegroup consisting of glyceryl tristearate, glyceryl trilaurate, glyceryltripalmitate, triglyceride suppository base, theobroma oil, coconut oiland mixtures thereof.